The complications of diabetes are responsible for increased mortality in patients with type 1 diabetes. The Diabetes Control and Complication Trial and its follow-up studies have demonstrated that the microvascular and, possibly, macrovascular complications of diabetes can be prevented by maintaining euglycemia. Unfortunately, maintaining normal or near normal glucose levels in most diabetic subjects is difficult and complicated by hypoglycemic episodes, which can be severe. The success of the Edmonton protocol for islet transplantation has renewed interest in cell replacement therapy as a means of achieving good glycemic control early in diabetes. This interest has been tempered, however, by the need for multiple transplants to achieve euglycemia. The reasons for this need are complex, but loss of trophic support prior to re-establishing the vascular supply of the islet and loss of extracellular matrix during the purification process alter islet engraftment and contribute to early loss of graft mass. We are proposing to develop a novel means of enhancing the engraftment, survival, and function of transplanted islets by transplanting islets on a poly(lactide-co-glycolide) scaffold capable of controlled drug delivery. To do this, a unique collaborative team with expertise in diabetes and islet biology, biomaterials and drug delivery, and islet transplantation has been formed. The specific aims are as follows. (1) To address the hypothesis that use of a polymer scaffold to provide extracellular matrix molecules to transplanted islets will prevent cell death and improve the function of the islets post-transplant. (2) To address the hypothesis that use of a polymer scaffold to enhance vascularization in transplanted islets through the localized and controlled delivery of angiogenic factors and/or endothelial cells will improve the survival and function of the islets post-transplant. Angiogenesis will be modulated in the transplanted islets by using the polymer scaffold to: (i) deliver vascular endothelial growth factor with or without platelet-derived growth factor and (ii) co-transplant endothelial cells with the islets. Use of polymer scaffolds is a novel and exciting approach to enhancing cell replacement therapy for diabetes that provides a unique means of enhancing the microenvironment of transplanted islets and has the potential to provide a major breakthrough in this important area of diabetes research/therapy.